Nucleophilic carbenes, 1,2,4-triazole

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

Attempted formation of the 4-silyl-substituted nucleophilic carbene (111) by deprotonation of the corresponding triazolium salt with KH led to the triazole (112), the product of apparent [1,2]-Si migration.A crossover experiment indicated that silyl transfer is intermolecular. 

In cooperation with Teles and colleagues, our research group has studied the triazole heterocycle as an alternative core structure of nucleophilic carbenes. First, the triazol-5-ylidene 12 (Fig. 9.3 see also Scheme 9.2) was synthesized and shown to be stable at temperatures up to 150 °C in the absence of air and moisture [22]. Compound 12 exhibited the typical behavior of a nucleophilic N-heterocyclic car-bene, and was found to be sufficiently stable to become the first commercially available carbene [23]. As shown in Scheme 9.2, the crystalline carbene was obtained from the corresponding triazolium salt precursor 13 by the addition of methanolate and subsequent thermal decomposition of the adduct 14 in vacuo via a-elimination of methanol [24]. 

There have been two published reports on the syntheses of stable 1,2,4-triazolyl carbenes. Thermal decomposition in vacuo of 5-methoxytriazoline 208 provided in quantitative yield l,2,4-triazol-5-ylidene 209, a stable carbene in the absence of oxygen and moisture <0381292>. This nucleophilic carbene 209 could react with a variety of alcohols, thiols, amines, oxygen, sulfur, selenium, isocyanantes, and metal carbonyls to form a myriad of addition products. Reactions of 1,2,4-triazolyl perchlorate salts 210 with base afforded stable nucleophilic 1,2,4-triazol-5-ylidenes 211, which could react with acetonitrile and elemental sulfur and selenium to yield addition products <03JOC5762>. 

DiazotriazoIe 28 (R = Ph) reacted with /-butyl alcohol and 2-propanol to give compounds 148 and 149 (Scheme 40) in comparable yields by carbenic C—H insertion and nucleophilic substitution, respectively [81DIS(B)(42)1892]. In the case of 2-propanol, an oxidation-reduction process, to give the parent triazole and acetone, was also observed to a smaller extent. Also, it was previously reported that 3-diazotriazole 28 (R = COOH) oxidizes primary and secondary alcohols to the corresponding aldehydes and ketones (1898LA33). 

N-Heterocyclic carbenes are an example of a family of nucleophilic catalysts [84-87]. For instance, the polymerization of p-butyrolactone was catalyzed by l,3,4-triphenyl-4,5-dihydro-l//,l,2-triazol-5-ylidene in the presence of methanol as an initiator [86]. This reaction was carried out in toluene at 80 °C. Nevertheless, an undesired elimination (Fig. 4) reaction was observed and control of the polymerization was lost. This issue was overcome by using ferf-butanol as a co-solvent, which reacts reversibly with the free carbene to form a new adduct. Owing to the decrease in the concentration of the free carbene, the elimination is disfavored and the polymerization is then under control provided that a degree of polymerization below 200 is targeted. As a rule, the reactivity of N-heterocyclic carbenes depends on their substituents. Hindered N-heterocyclic carbenes turned out to be not nucleophilic enough for the ROP of sCL. Recently, it was shown that unencumbered N-heterocyclic carbenes were more efficient catalysts [87]. 

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

The Enders research group realised that an increased nucleophilicity on the carbene carbon atom would improve the benzoin condensation overall and might give the necessary impetus to break the apparent deadlock by initially increasing the yield and in its wake the chiral resolution. This was achieved by switching to triazole based NHC instead of the less nucleophilic thiazole based NHC (see Figure 6.3) [17-19]. The scheme proved to be successful as an ee of 75% (R) in 66% yield and a catalyst loading of 1.25 mol% could be achieved. 

It will be interesting to see how general this behaviour is. Enders [39,40] reported that triazol-2-ylidene 37 reacted with oxygen, sulfur and selenium to give the expected urea derivatives in 54%, 98%, and 88% yields respectively (Scheme 12). The reaction with sulfur in benzene to give thiourea derivatives is rapid and is often used as a test of carbene formation. It is presumably initiated by nucleophilic attack by the carbene on Sg. 

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